Gene therapy for the treatment of hip prosthesis loosening: adverse events in a phase 1 clinical study.
Revision surgery for loosened hip prostheses is a heavy burden for elderly patients with comorbidity. As an alternative to surgery we performed a study to stabilize the prosthesis by percutaneous cement injection after removing inflammatory tissue with an intraarticular virus-directed enzyme prodrug approach. Twelve elderly patients with debilitating pain from a loosened hip prosthesis were included in a phase 1 dose-escalating clinical study. The patients were admitted to the hospital for 10 days for an intraarticular vector and prodrug injection, and subsequently for a percutaneous bone cement injection. This paper reports the adverse and serious adverse events of the study. After prodrug injection 9 of 12 patients had gastrointestinal adverse events (nausea, vomiting, and diarrhea), and 8 patients had hepatic adverse events (rise in aspartate aminotransferase and alanine aminotransferase). Five patients developed anemia (World Health Organization grade 1 or 2) from hematomas after cement injection. There were four serious adverse events in the first 6 months after vector injection, but these were not related to gene therapy as judged by an independent safety committee. There was no dose-limiting toxicity. However, the extensive comorbidity in these patients makes it difficult to fully establish the safety of the approach in this small and heterogeneous patient population.
de Poorter
Jolanda J
JJ
Department of Orthopedics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Hoeben
Rob C
RC
Obermann
Willem R
WR
Huizinga
Tom W J
TW
Nelissen
Rob G H H
RG
D000256:Adenoviridae; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D019644:Arthroplasty, Replacement, Hip; D001388:Aziridines / Q000008:administration & dosage / Q000009:adverse effects*; D029968:Escherichia coli Proteins; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects*; D006622:Hip Prosthesis / Q000009:adverse effects*; D006801:Humans; D008297:Male; D009601:Nitroreductases; D059408:Pain Management; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects*
D000970:Antineoplastic Agents; D001388:Aziridines; D029968:Escherichia coli Proteins; D011355:Prodrugs; C100099:tretazicar; C116054:NfsB protein, E coli; D009601:Nitroreductases